Is SCN8A p.Pro1797Ser (c.5389C>T) pathogenic?

SCN8A p.Pro1797Ser (c.5389C>T) is classified Uncertain significance in SCN8A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-10). AlphaMissense: ambiguous (0.3657); Very rare (popmax 0.00891%, eas); Associated with early-infantile DEE.

What condition is associated with SCN8A p.Pro1797Ser (c.5389C>T)?

SCN8A p.Pro1797Ser (c.5389C>T) is associated with early-infantile DEE (ClinVar).

How common is SCN8A p.Pro1797Ser (c.5389C>T) in the general population?

SCN8A p.Pro1797Ser (c.5389C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about SCN8A p.Pro1797Ser (c.5389C>T)?

AlphaMissense predicts ambiguous (score 0.3657) — an in-silico prediction, not a clinical call.

SCN8A p.Pro1797Ser

c.5389C>T · rs772562118 · VCV1747203

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3657 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

early-infantile DEE

Computational evidence

Protein change
AlphaMissense	0.3657	ambiguous
REVEL	0.849	moderately pathogenic-leaning
SaProt	LLR -9.24	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 284 bp · p 1.4e-11 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,886 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000248% 4/1,613,506 alleles · very rare exomes 3/1,461,346 · genomes 1/152,160 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SCN8A
Protein: p.Pro1797Ser
Coding: c.5389C>T
MANE Select: NM_001330260
dbSNP: rs772562118
Type: single nucleotide variant
Location: chr12:51806875 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.90 · 7 PDB

Full SCN8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

early-infantile DEE — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SCN8A p.Pro1797= Benign/Likely benign ★★ same residue
SCN8A c.615-1G>A Pathogenic ★★★ same condition
SCN8A p.Arg1872Gln Pathogenic ★★★ ⚠ same condition
SCN8A p.Asn418Asp Likely pathogenic ★★★ same condition
SCN8A p.Glu1218Lys Pathogenic ★★★ same condition
SCN8A p.Ile1631Thr Likely pathogenic ★★★ same condition
SCN8A p.Ser845Cys Likely pathogenic ★★★ ⚠ same condition
SCN8A p.Ser845Phe Likely pathogenic ★★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/scn8a-p-pro1797ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown